Background: Sterol regulatory element-binding protein 1 (SREBP1) is a key regulator of lipid metabolism. However, its role in osteoclast differentiation and bone resorption remains unclear. This study investigated the function of SREBP1-mediated lipid metabolic remodeling in osteoporosis.

Methods: An ovariectomized (OVX) mouse model and SREBP1 conditional knockout mice were used to evaluate bone metabolism in vivo. RAW264.7 cells were stimulated with Receptor Activator of Nuclear Factor κB Ligand (RANKL) to induce osteoclast differentiation in vitro. Fatostatin and oleic acid were used to modulate SREBP1 activity and lipid metabolism.

Results: OVX mice showed significantly increased SREBP1 expression compared with the Control group (p < 0.05). Lipid synthesis enzymes Fatty Acid Synthase (FASN), Acetyl-CoA Carboxylase (ACC), and Stearoyl-CoA Desaturase 1 (SCD1) were also elevated (p < 0.05). Serum bone resorption markers C-terminal Telopeptide of Type I Collagen (CTX-I) and Tartrate-Resistant Acid Phosphatase (TRACP) were increased (p < 0.05), whereas bone formation markers Procollagen Type I N-terminal Propeptide (PINP) and Bone-specific Alkaline Phosphatase (B-ALP) were reduced (p < 0.05). These alterations were partially reversed in OVX+SREBP1 knockout mice (p < 0.05). In vitro, SREBP1 expression progressively increased during RANKL-induced osteoclast differentiation (p < 0.05). This increase correlated with elevated Nuclear Factor of Activated T Cells 1 (NFATC1), Tartrate-Resistant Acid Phosphatase (TRAP), and Cathepsin K (CTSK) expression (p < 0.05). Fatostatin significantly reduced osteoclast formation and bone resorption activity (p < 0.05), and suppressed lipid metabolism enzyme expression (p < 0.05). Oleic acid supplementation partially restored osteoclast differentiation and function (p < 0.05).

Conclusion: SREBP1 promotes osteoclast maturation and bone resorption by regulating lipid metabolism. Targeting SREBP1 or modulating fatty acid metabolism may provide a potential therapeutic strategy for osteoporosis.